Abstract
Proteins containing intrinsically disordered regions (IDRs) are ubiquitous within biomolecular condensates, which are liquid-like compartments within cells formed through liquid–liquid phase separation (LLPS). The sequence of amino acids of a protein encodes its phase behaviour, not only by establishing the patterning and chemical nature (e.g., hydrophobic, polar, charged) of the various binding sites that facilitate multivalent interactions, but also by dictating the protein conformational dynamics. Besides behaving as random coils, IDRs can exhibit a wide-range of structural behaviours, including conformational switching, where they transition between alternate conformational ensembles. Using Molecular Dynamics simulations of a minimal coarse-grained model for IDRs, we show that the role of protein conformation has a non-trivial effect in the liquid–liquid phase behaviour of IDRs. When an IDR transitions to a conformational ensemble enriched in disordered extended states, LLPS is enhanced. In contrast, IDRs that switch to ensembles that preferentially sample more compact and structured states show inhibited LLPS. This occurs because extended and disordered protein conformations facilitate LLPS-stabilising multivalent protein–protein interactions by reducing steric hindrance; thereby, such conformations maximize the molecular connectivity of the condensed liquid network. Extended protein configurations promote phase separation regardless of whether LLPS is driven by homotypic and/or heterotypic protein–protein interactions. This study sheds light on the link between the dynamic conformational plasticity of IDRs and their liquid–liquid phase behaviour.
Highlights
The cell interior contains thousands of different biomolecules, which need to be organized in space for the cell to function
One of the key cellular mechanisms to control the spatial organization of components is formation and dissolution of biomolecular condensates—membraneless compartments sustained by the physical chemistry of liquid–liquid phase separation (LLPS) [1,2,3]
Based on the ability of intrinsically disordered regions (IDRs) to exhibit large conformational fluctuations [29,30] and the dominant role of multivalency in LLPS [10,98], we develop a minimal coarse grained model that allows us to modulate the structural plasticity of multivalent IDRs
Summary
The cell interior contains thousands of different biomolecules (e.g., multivalent proteins and RNAs), which need to be organized in space for the cell to function. Besides compartmentalisation of the cytoplasm [2,8,9,10,11,12], LLPS is involved in genome silencing [13,14,15], the formation of pathological aggregates such as amyloid fibrils [3,16,17,18], and helping cells to sense and react to environmental changes [19] Novel biological features, such as the ability of condensates to buffer protein concentrations against gene expression noise [20] continue being discovered. Due to their conformational versatility, IDRs can promote LLPS by acting as inert but highly flexible linkers that connect modular domains [34,35]
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